Head and neck squamous cell carcinoma (HNSCC) is an ominous cancer with more than 48,000 new cases diagnosed annually in the US. Gene-directed enzyme prodrug therapy (GDEPT) using adenovirus with herpes simplex virus thymidine kinase (Ad.HSVtk) in conjunction with ganciclovir (GCV) is effective in HNSCC tumor management, however transient gene expression, dissemination of viruses to non-target organs, and multiple injections required for both the virus and drug limit therapeutic utility. Matrix-mediated delivery of adenoviruses by silk-elastinlike protein polymer (SELP) hydrogels increase transfection efficiency in tumors, localize transgene expression, and enhance therapeutic efficacy. Matrix metalloproteinases (MMPs) are known to degrade and remodel the tumor extracellular matrix. By introducing MMP responsive amino acid sequences at precise locations in SELPs, it is possible to control the degradation of SELPs and release of both adenoviruses and GCV. The following Specific Aims will be addressed: 1) Synthesize and characterize silk- elastinlike polymers containing MMP degradable sequences in the backbone. 2) Evaluate the influence of MMP responsive sequences on degradation properties of SELP hydrogels and adenoviral release in vitro. 3) Evaluate the influence of MMP degradable sequences on improvement of transfection efficiency, duration of transgene expression, biodistribution, therapeutic efficacy, and toxicity in vivo. The new polymers are designed to enhance the efficacy of GDEPT while reducing toxicity and the need for multiple injections of both the virus and the drug, ultimately enhancing therapeutic outcome for patients with HNSCC.